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T. Giores, M.A., Ph.D.

Co-Director, Johns Hopkins University School of Medicine

This means that specific procedures are required to monitor the stability of the response of the mass spectrometer over the analysis of large series of samples (typically a few hundred to a few thousand) and to check the quality of the data. There are about 8000 known metabolites in blood, and about 1000 of those can be identified in untargeted metabolomics experiments. Many more signals are detected but are still unknown, because of the lack of reference mass spectra in metabolite databases and of commercial standards needed for their identification. Applications of metabolomics to understanding cancer development Currently, applications of metabolomics to cancer research are quite diverse. Tumour samples have been compared with normal tissues to identify metabolites that vary in their concentrations in the two types of tissues. Metabolic alterations in tumour samples were investigated in 11 studies for 7 cancer types, and a meta-analysis was performed of the results from each individual study [4]. Some metabolites were differentially abundant in tumour samples and normal tissues for multiple cancer types; these included taurine, acylcarnitine, kynurenine, and lactate, reflecting common alterations in pathways notably related to sugar metabolism, glutathione metabolism, and fatty acid biosynthesis. Similarly, the comparison of metabolic profiles of 60 primary cancer cell lines from 9 tumour types showed that several pathways were commonly affected in the different cell lines, and that glycine was highly correlated with rate of proliferation [5], leading to the recognition of the oncogenic role of glycine decarboxylase. Metabolomics and fluxomics have been applied to tumour cell cultures to identify metabolic alterations and adaptations, which are now recognized as a hallmark of cancer [6]. As an example, the systematic overexpression of individual enzymes in the 12 steps linking extracellular glucose to excreted lactate combined with flux analysis led 202 to the identification of 4 steps in the pathway that enhance glycolysis in the tumour cell and underlie the Warburg effect [7]. Metabolomics is also used to compare metabolic profiles of cells treated with various enzyme inhibitors or drugs. Koningic acid was identified as a highly specific inhibitor of glyceraldehyde 3-phosphate dehydrogenase, a rate-controlling enzyme in the glycolytic pathway, with limited perturbations of other metabolic pathways [8]. Many of these metabolites are affected by different types of cancer, whereas others appear to be more specific for a particular cancer type; for example, bilirubin and bile acids are associated with hepatocellular carcinoma. Most of these metabolites are common, universally occurring metabolites, which can also be influenced by various confounding factors, such as other diseases, age, or body mass index (see Chapter 2. Therefore, there is little likelihood that any of these metabolites can be used on their own as a biomarker for diagnosis, but they may have applications in the context of panels made up of several metabolites, proteins, and/or clinical biomarkers. Less-common biomarkers, which are often present at low concentrations in blood or urine, may be more specific for a particular cancer type and better predictors of cancer or of specific stages of the cancer. A conjugated steroid, 27-nor-5cholestane-3,7,12,24,25 pentol glucuronide, was significantly upregulated in the serum of women with epithelial ovarian cancer in both early-stage and late-stage patients when compared with healthy women or women with benign ovarian tumours [12]. These two metabolites also had higher diagnostic performance than -fetoprotein for early-stage hepatocellular carcinoma. Applications of metabolomics to prospective epidemiological studies are relatively recent. The earliest application of metabolomics within a prospective study involved 189 individuals who developed type 2 diabetes and 189 matched controls from the Framingham Offspring Study [16]. Subsequently, more studies were performed on risk of type 2 diabetes, and a recent metaanalysis of results from eight original publications showed consistent associations of levels of these five amino acids with the risk of developing type 2 diabetes [17]. The bile acid glycochenodeoxycholate was associated with risk of colorectal cancer in women. These prospective studies, which show associations of blood metabolites several years before diagno-. Arrows indicate the direction of the associations: positive association, negative association, and inconsistent direction ( First, few of these results have yet been replicated in independent cohorts [3,12]. They will need to be confirmed in future studies, as has been done for type 2 diabetes.

Recent advances in diagnostic tools using multigene panel testing have enabled the simultaneous and more affordable analysis of multiple cancer predisposition genes. Health system, ethnic, and socioeconomic disparities in access to risk assessment still exist, especially in low- and middle-income countries, and add to the complexity of enabling universal access to this important strategy to reduce the global cancer burden. The identification of individuals and families with hereditary cancer is an important opportunity for cancer prevention [1]. Carriers of such variants have significantly higher risks of developing multiple cancer types, often at an early age, compared with the general population. Therefore, these cases contribute a significant proportion of the cancer burden worldwide, given that lifetime cancer risks in these individuals may reach up to 80%. This enables early and frequent screening to detect smaller, more curable cancers, and to propose cancer prevention measures (Box 6. Despite such high risks and the availability of cancer risk-reducing interventions. The phenotypic effect is heterogeneous for most variants associated with hereditary cancer. Genetic variants can be classified according to their frequency and the associated risk of cancer. In addition, there are geographical, population-derived differences in variant type and frequency among different regions of the world, and founder mutations account for a substantial fraction of the cancer burden in certain regions (Table 6. Therefore, characterization of the mutational landscape of cancer predisposition genes and variant penetrance is of great importance. Although specific cancer predisposition syndromes are clearly identified (Table 6. As tumour genetic testing becomes more common, previously unrecognized germline mutations will be detected, and the percentage of cancers accounted for by high or moderate genetic risk as a result of de novo mutations will be better understood. There is significant heterogeneity in cancer risks associated with pathogenic or likely pathogenic variants in cancer predisposition genes, and management differs according to the penetrance of each variant. Advances in sequencing technology have enhanced knowledge about the genes and pathogenic or likely pathogenic variants associated with hereditary cancer and have increased access to more affordable and comprehensive genetic testing. Options are available for cancer risk reduction in carriers, including lifestyle changes, enhanced surveillance, chemoprevention, and risk-reduction surgery. Genetic/genomic cancer risk assessment is a standard-of-care multidisciplinary process that ideally involves genetic counselling, experienced cancer risk consultants, and medical/surgical risk management teams. Despite major advances in the field, the remaining challenges include difficulties in the breadth of variants and their curation, limited accuracy of the associated risk estimation and establishment of clinical utility, limited access to professional genetic counselling and testing, and the need for professional education about genetics and genomics and training of multidisciplinary teams. Genetic risk categories in hereditary cancer and their characterization according to penetrance, actionability, screening and management recommendations, and implications for family members. Clinical utility increases with higher cancer risk predisposition; the gradient in the arrow denotes the potential significant overlap between the categories. Odds ratios are presented as estimates of the generalized odds over the baseline population for organ-specific cancer risk. More studies, especially on genes in the low- and moderate-risk categories, are needed to better clarify the associated cancer risks and penetrance. It is important to note that penetrance and expressivity can widely vary with specific mutations within the same gene. High risk Clinical utility Penetrance: high; causes a well-known cancer syndrome with well-defined cancer risks. Actionability: high; evidence-based risk-reducing guidelines exist for at least one organ system. Penetrance: moderate; organ-specific cancer risks are defined for at least one cancer site. Implications for other family members: challenging, may be difficult to determine. Screening and management recommendations: based on empirical risk estimates and case-by-case literature and laboratory data review. Moderate risk Low risk or in newly identified or very rare genes for which validation studies are required, and the pervasive conundrum of variants of uncertain significance.

More material can be obtained at the end of the plunger or the needle (or tip of syringe) after removing the plunger and the needle. Have culture medium ready (if available) and labeled in the same way as the slides. For safety, the spleen should be palpable at least 3 cm below the costal margin on expiration. Use an alcohol swab to clean the skin at the site of aspiration and allow the skin to dry. The actual aspiration is done as follows: pull the syringe plunger back to approximately the 1ml mark to apply suction and with a quick in-and-out movement push the needle into the spleen to the full needle depth and then withdraw it completely, maintain suction throughout. For young, restless children, have two assistants hold the child (arms folded across the chest, with shirt raised to obstruct the line of vision, and pelvis held firmly). Replace the cap on the tube and invert to wash splenic material on the side of the tube. Expel material gently onto glass slides, holding the needle tip on the surface of the slide. Remove the needle and use the end of it to obtain additional material from the tip of the syringe and spread it on slides. Further material found on the end of the plunger may be dabbed directly onto a slide and spread. Write the time of aspiration on the patient`s chart with the instructions: "Record pulse and blood pressure every half hour for 4 hours, then every hour for 6 hours. Take the slides (and medium) to the laboratory for preparation and microscopic examination. Annex 6: Preparation and Examination of Aspirates Preparation of the aspirates Prepare thin films of the splenic aspirate material or lymph gland fluid. Spread the films on a clean glass slide immediately after collection before the material clots. Slides are stained with Giemsa as for a thin malaria film and examined under oil immersion. The methanol must be stored in a tightly closed bottle to prevent absorption of water. Never pour the stain off the slides, otherwise the surface scum will stick to the film and spoil if for microscopic examination. If there is no inbuilt light source, adjust the flat side of the mirror to reflect the light up through the condenser. A slight resistance and a click are felt as the objective moves to the correct position. Never place the slide on the stage when the x40 or x100 (oil immersion) objectives are in position as this may scratch the lenses. Scan the film and select a part that is well stained, free of staining debris and well populated with white blood cells. For example, start at the selected site and move horizontally to the top right hand corner.

Recently it is shown that different forms of sheep paratuberculosis have differential expression of pattern recognition receptors5, including Toll-like receptors. Intestine: Enteritis, granulomatous, diffuse, marked, with villar blunting, lymphangitis, and crypt loss. The problem is further exacerbated in small ruminant herds where diarrhea is not a typical clinical sign. Clinical disease occurs 7 due to the abundant granulomatous inflammation, and the lesions are often restricted to the ileum,12 though the transmural granulomatous infiltration may also be observed in the colon and the organism has been cultured from a variety of organs. The pathology and pathogenesis of paratuberculosis in ruminants and other species. The association of detection method, season, and lactation stage on identification of fecal shedding in mycobacterium avium ssp. Differential expression of pattern recognition receptors in the three pathological forms of sheep paratuberculosis. Description and classification of different types of lesions associated with natural paratuberculosis infection in sheep. Differential cytokine gene expression profiles in the three pathological forms of sheep paratuberculosis. Variation in the immuno-pathological responses of lambs after experimental infection with different strains of Mycobacterium avium subsp. History: this specimen is one of a number of hunter-killed caribou that were submitted to the Canadian Cooperative Wildlife Health Centre due to concerns about the quality of the meat. In this case, only the head was submitted with the concern being the presence of "pus in the nose". Over the bridge of the nose about 2cm behind the nasal plenum there is a 3cm diameter area of thickened skin covered by a crusty surface exudate. On section of the head, the anterior 4cm of both nasal cavities contain a large amount of muco-purulent yellowbrown tenacious exudate. S e g m e n t a l l y, the epidermis is thickened and composed of or replaced by a variably thick layer of parakeratotic hyperkeratosis, fibrin, necrotic debris, bacterial colonies, pustules, fragmented hair shafts and vacuolated epithelial cells. A thick pale eosinophilic to pale blue capsule surrounds the bradyzoites contained within a parasitophorus vacuole. Occasionally cysts, particularly within the more superficial layers of the skin, appear to be dead and are infiltrated with macrophages, and multinucleate giant cells with smaller numbers of lymphocytes and plasma cells. Whether these are all truly distinct species is unclear as currently the life cycle of only a small number of 3-1. Skin, caribou: the dermis is markedly expanded by numerous apicomplexan cysts which efface adnexa; the overlying epidermis is multifocally necrotic and diffusely and severely hyperkeratotic. The domestic cat is the definitive host for the 3 species with a known life cycle, but the definitive host for the B. Over the course of 3 years besnoitiosis spread to mule deer (Odocoileus hemionus hemionus), reindeer (Rangifer tarandus tarandus) and a second isolated group of caribou. Twenty-eight caribou, 10 mule deer and 3 reindeer were euthanized or died as a result of this epizootic. In wild woodland caribou, besnoitiosis appears to be a relatively common (23% infection rate in one study) chronic and mild disease. Haired skin: Hyperplasia and hyperkeratosis, epidermal, diffuse, severe, with segmental epidermal necrosis and numerous mixed bacterial colonies. Conference Comment: Most slides contain two sections of skin in this case which are variably affected with epidermal necrosis, parakeratotic hyperkeratosis and epidermal hyperplasia. While the protozoal cysts are diffuse throughout all areas, the most severe areas of hyperkeratosis also contain numerous aggregrates of mixed bacteria 3-3.